A novel mutation in the DNASE1 gene is related with protein instability and decreased enzyme activity in thyroid autoimmunity

Dittmar, Manuela; Bischofs, Christian; Matheis, N.; Poppe, Robert; Kahaly, George J.

doi:10.1016/j.jaut.2008.09.005

Cited by 36 publications

(22 citation statements)

References 30 publications

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“…46 Indeed, mutation in the DNAse gene was found associated with autoimmune disease as in humans SLE. 47 In SLE, neutrophils are highly prone to form NET on binding to anti-RNP autoantibodies, a hallmark of this disease. 10 It has been recently shown that pDCs are able to respond to the DNA component of NET and to produce abundant type I IFN, an event that eventually promote further immune system activation.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity

Sangaletti

Tripodo

Chiodoni

et al. 2012

Blood

356

314

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Antineutrophil cytoplasmic antibodies (ANCAs) target proteins normally retained within neutrophils, indicating that cell death is involved in the autoimmunity process. Still, ANCA pathogenesis remains obscure. ANCAs activate neutrophils inducing their respiratory burst and a peculiar form of cell death, named NETosis, characterized by formation of neutrophil extracellular traps (NETs), decondensed chromatin threads decorated with cytoplasmic proteins endorsed with antimicrobial activity. NETs have been consistently detected in ANCA-associated small-vessel vasculitis, and this association prompted us to test whether the peculiar structure of NET favors neutrophil proteins uploading into myeloid dendritic cells and the induction of ANCAs and associated autoimmunity. Here we show that myeloid DCs uploaded with and activated by NET components induce ANCA and autoimmunity when injected into naive mice. DC uploading and autoimmunity induction are prevented by NET treatment with DNAse, indicating that NET structural integrity is needed to maintain the antigenicity of cytoplasmic proteins. We found NET intermingling with myeloid dendritic cells also positive for neutrophil myeloperoxidase in myeloperoxidase-ANCA-associated microscopic poliangiitis providing a potential correlative picture in human pathology. These data provide the first demonstration that NET structures are highly immunogenic such to trigger adaptive immune response relevant for autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity

Sangaletti

Tripodo

Chiodoni

et al. 2012

Blood

356

314

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“…It catalyzes DNA hydrolysis by cleaving double-stranded DNA. The activity of this enzyme was lowered in patients with PAS compared to healthy subjects (21,22). Such a deficiency in DNase 1 may result in reduced or delayed removal of DNA from nuclear antigens and, thereby, may promote disease susceptibility to autoimmune disorders.…”

Section: Innate Immunity and The Enzyme Deoxyribonucleasementioning

confidence: 94%

Polyglandular autoimmune syndromes

Kahaly

2009

European Journal of Endocrinology

206

106

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The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (PAS type I) and a relatively common adult type with (PAS II) or without adrenal failure (PAS III). First clinical manifestation of PAS I usually occurs in childhood, whereas PAS II mostly occurs during the third and fourth decades. PAS I is caused by mutations in the autoimmune regulatory (AIRE) gene on chromosome 21 and is inherited in an autosomal recessive manner. Mutations in the AIRE gene result in defect proteins which cause autoimmune destruction of target organs by disturbing the immunological tolerance of the patients. Genetic testing may identify patients with PAS I, but not those with PAS II/III. For PAS II/III, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T lymphocyte antigen gene, and the protein tyrosine phosphatase nonreceptor type 22 gene on chromosomes 6, 2 and 1 respectively. Actual diagnosis of PAS involves serological measurement of organ-specific autoantibodies and subsequent functional testing. Management of patients with PAS including their family relatives is best performed in centres with special expertise in autoimmune endocrine disorders.

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“…Possible implications of the nonsynonymous SNPs in DNASE1 in relation to the etiology of SLE Patients with SLE harbor mutations resulting in a lack or reduction of DNase I activity (Yasutomo et al, 2001;Dittmar et al, 2009), and similarly, DNase I-deficient mice develop SLE (Napirei et al, 2000). Furthermore, it has been reported that levels of serum DNase I activity are lower in SLE patients than in healthy subjects (Chitrabamrung et al, 1981;Sallai et al, 2005;Dittmar et al, 2007;MartineaValle et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that DNase I-deficient mice develop an SLE-like syndrome (Napirei et al, 2000). In addition, a novel nonsense mutation (Yasutomo et al, 2001) and several missense (Dittmar et al, 2009) mutations resulting in the abolishment/reduction of the activity have been identified in patients with autoimmune diseases. These findings suggest that a single-nucleotide polymorphism (SNP) in DNASE1, producing forms with loss of function or markedly reduced activity, might be substantially responsible for the genetic background determining susceptibility to autoimmune diseases through failure in the breakdown of chromatin during apoptosis and/or necrosis (Counis and Trriglia, 2000;Mizuta et al, 2006;Napirei et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Identification of the Functional Alleles of the Nonsynonymous Single-Nucleotide Polymorphisms Potentially Implicated in Systemic Lupus Erythematosus in the Human Deoxyribonuclease I Gene

Kimura-Kataoka

Ueki

Takeshita

et al. 2014

DNA and Cell Biology

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In the present study, we have extensively continued our previous investigations of the nonsynonymous single-nucleotide polymorphisms (SNPs) in the human DNase I (DNASE1) gene potentially relevant to systemic lupus erythematosus (SLE); therefore, all of the 58 nonsynonymous SNPs registered in the NCBI dbSNP database could be evaluated and it could be checked as to whether these SNPs might serve as a functional SNP. From a compiled expression analysis of the amino-acid-substituted DNase I corresponding to each of the SNPs, it was possible to sort them into 23 SNPs while not affecting the activity: 12 abolishing it, 14 reducing it, and 9 increasing it. Among a total of 58 nonsynonymous SNPs, only 4 SNPs exhibited genetic polymorphisms in some of the populations examined; a minor allele producing a loss-of-function variant of each SNP was not distributed in 14 different populations derived from three ethnic groups. It could be assumed that a minor allele of these functional SNPs, despite their remarkably low genetic heterogeneity, could directly serve as a genetic risk factor for SLE. Furthermore, among the human DNase family genes, it seems that DNASE1 is able to tolerate the generation of nonsynonymous SNPs, and that the amino-acid substitutions resulting from the SNPs in DNASE1 easily alter the activity.

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A novel mutation in the DNASE1 gene is related with protein instability and decreased enzyme activity in thyroid autoimmunity

Cited by 36 publications

References 30 publications

Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity

Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity

Polyglandular autoimmune syndromes

Identification of the Functional Alleles of the Nonsynonymous Single-Nucleotide Polymorphisms Potentially Implicated in Systemic Lupus Erythematosus in the Human Deoxyribonuclease I Gene

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